Ischemia of the heart is the reduction of blood flow to cardiac tissue which can result in dysrhythmic conditions, e.g. ventricular arrhythmia and ventricular fibrillation, and cell death. Such dysrhythmic conditions are the result of the asynchronous excitability states created between normal and ischemic-injured cardiac cells which, in turn, caused a disruption of the normal ion transport channels within the cardiac tissue.
Ventricular fibrillation is generally considered to be a severe extension of less harmful ventricular arrhythmias. Arrhythmia rises to the level of fibrillation when this disruption results in action potential and conduction inhomogeneities that critically desynchronize normal excitation and contraction coupling over a sufficient portion of the heart (Bacaner et al., "Potassium Channel Blockade: A Mechanism for Suppressing Ventricular Fibrillation", Proc. Nat'l. Acad. Sci. U.S.A., Vol. 83:2223-2227, April 1986:Medical Sciences).
However, despite the apparent link between arrhythmia and fibrillation, it has been found that lidocaine and procainamide, Class I antiarrhythmic agents, do not have antifibrillatory activity. These agents prevent ventricular arrhythmias but are unable to suppress ventricular fibrillation as disclosed by N. Cook, "The Pharmacology of Potassium Channels and Their Therapeutic Potential", TIPS, January 1988; Vol. 9: p. 21-28.
It is also interesting to note that similar results have been observed with certain anti-ischemic agents. For example, certain calcium channel blockers and thromboxane receptor antagonists have been identified as capable of significantly reducing infarct size and thus are potentially useful as anti-ischemic agents. Surprisingly, reduction of infarct size, accomplished via reperfusion (restoration of blood flow to previously injured cardiac tissue), does not dictate suppression of fibrillation. Likewise, reperfusion can be provided to an ischemic heart by various new surgical (bypass), mechanical (angioplasty) and thrombolytic means in a sufficiently timely fashion so as to save much of the ischemia-injured tissue.
The Bacaner et al. report further discloses that bretylium and bethanidine have been found useful in decreasing conduction inhomogeneities in the ischemic-injured heart resulting in an increase in action potential duration and decreased fibrillation. This antifibrillatory action is attributed to blockade of one or more of the potassium channels in the cells of the heart. Thus, potassium channel blockers are expected as a class to be useful as antifibrillatory agents. In fact, P. Siegl, et al., "Effects of ATP-Sensitive Potassium Channel Modulators, Glyburide and BRL 34915, on Ischemia-Induced Fibrillation in Isolated Rat Hearts", FASEB Journal, Vol. 3, #3, A3607 (1989), have observed profibrillatory activity for potassium channel activators such as pinacidil and BRL 34915 (cromakalim).
Petersen, in U.S. Pat. No. 4,057,636, discloses compounds of the formula ##STR2## wherein R.sub.2 can be hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy. These compounds are stated to be useful as antihypertensive agents.
Petersen et al., in "Synthesis and Hypotensive Activity of N-Alkyl-N"-Cyano-N'-Pyridylguanidines", Journal of Medicinal Chemistry, 1978, Vol. 21, No. 8, disclose compounds as above in U.S. Pat. No. 4,057,636 but wherein the pyridyl group has been replaced by a phenyl ring. Petersen et al. further disclose that such phenyl compounds are either inactive or only weakly active as antihypertensive agents.